Targeting Glucose Metabolism: Synergistic Strategies to Enhance Apoptosis and Immune Activation in Hepatocellular Carcinoma Treatment
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE295520 | GEO | 2025/04/30
REPOSITORIES: GEO
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Project description:Pyroptosis is an emerging programmed cell death with great potential in antitumor immunotherapy. However, the actual application of pyroptosis is hampered by its nonspecificity and inefficiency. In this study, a reactive oxygen species (ROS) responsive potassium (K+) ionophore-based nanoplatform rPPAA18C6 is constructed based on the triblock polymers PEG-PPBAEM-PAA18C6 to potentiate cancer pyroptosis and immunotherapy via the K+ metabolic disturbance mediated endoplasmic reticulum (ER) stress. The PEG (P) is used to prolong the circulation time in vivo, PPBAEM (r) is used to target the tumor cells and responds to the higher ROS, and PAA18C6 is used to perturb of K+ homeostasis. Moreover, rPPAA18C6 can also function as a drug carrier for chemodrug (doxorubicin, Dox). We find that rPPAA18C6@Dox provokes immune responses in melanoma (B16F10) via pyroptosis-related immunogenic cell death (ICD), in which damage-associated molecular patterns (DAMPs) are released to promote maturation of dendritic cells (DCs), activate cytotoxic T lymphocytes (CTLs), and convert immunosuppressive “cold” tumor to immunogenic “hot” tumor. Moreover, the combined therapy with anti-PD-L1 exhibits apparent tumor suppression far more than expected, suggesting a powerful candidate of rPPAA18C6@Dox for high-efficient immune checkpoint blockade (ICB) therapy. This study thus provides a promising strategy to specifically initiate pyroptosis and potentiate immunotherapy by perturbation of K+ metabolism via a smart nanoplatform.
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Project description:The induction of immunogenic cell death (ICD) impedes tumor progression via both tumor cell-intrinsic and -extrinsic mechanisms, representing a robust therapeutic strategy. However, ICD-targeted therapy remains to be explored and optimized. Through kinome-wide CRISPR-Cas9 screen, NUAK1 is identified as a potential target. The ICD-provoking effect of NUAK1 inhibition depends on the production of reactive oxygen species (ROS), consequent to the downregulation of NRF2-mediated antioxidant gene expression. Moreover, the mevalonate pathway/cholesterol biosynthesis, activated by XBP1s downstream of ICD-induced endoplasmic reticulum stress, functions as a negative feedback mechanism. Targeting the mevalonate pathway with CRISPR knockout or HMGCR inhibitor simvastatin amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol dampers ROS, ICD and therefore tumor suppression. The combination of NUAK1 inhibitor and statin enhances the efficacy of anti-PD-1 therapy. Collectively, our study unveils the promise of blocking the mevalonate-cholesterol pathway in conjunction with ICD-targeted immunotherapy.
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Project description:Background: Despite current therapeutic treatments including surgery, chemotherapy, radiotherapy and recently immunotherapy, the mortality rate of lung cancer stays high. Regarding lung cancer, epigenetic modifications altering cell cycle, angiogenesis and programmed cancer cell death are therapeutic targets to combine with immunotherapy to improve treatment success. In a recent study, we uncovered a dual function of a molecule called QAPHA ((E)-3-(5-((2-cyanoquinolin-4-yl)(methyl)amino)-2-methoxyphenyl)-N-hydroxyacrylamide) as both a tubulin polymerization and HDAC inhibitors. Here, we investigate the impact of this novel dual inhibitor on the lung cancer immune response. Methods: To elucidate the mechanism of action of QAPHA, we conducted a chemical proteomics analysis. Using an in vivo mouse model of lung cancer (TC-1 tumor cells), we assessed the effects of QAPHA on tumor regression. Tumor infiltrating immune cells were characterize by flow cytometry. Results In this study, we first show that QAPHA can inhibit HDAC6, leading to upregulation of HSP90, cytochrome C and caspases, found by proteomic analysis. We also confirm that QAPHA induces immunogenic cell death (ICD) by upregulating HMGB1 in vitro and demonstrated its effectiveness as a vaccine in vivo. Remarkably, even at a low concentration (0.5mg/kg), QAPHA achieved complete tumor regression in approximately 60% of intratumorally treated mice, establishing a long-lasting anticancer immune response. Moreover, QAPHA treatment promoted infiltration of neutrophils in the treated mice, reflecting inflammatory cell death promoted. Very interestingly, we show that QAPHA is also able to upregulate MHC-II expression on TC-1 tumor cells in vitro and in vivo. This process participates to the recruitment of CD4+ NKG2D+ CRTAM+ Perforin+ T cells in tumor infiltrate, defined as cytotoxic CD4+ T cells (CD4+ CTL). Finally, we show that tumor regression is strongly correlated to MHC-II expression level on tumor cell and CD4+ CTL infiltrate. Conclusion Collectively, our findings shed light on the discovery of a new multi-target inhibitor able to induce ICD and MHC-II upregulation in TC-1 tumor cell. These two processes participate to enhance a specific CD4+ cytotoxic T cell-mediated anti-tumor response in vivo in our model of lung cancer. This breakthrough suggests the potential of QAPHA as a promising therapeutic agent for cancer treatment.
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Project description:Proteasome inhibitor bortezomib (BTZ) induces apoptosis in myeloma (MM) cells, and has transformed patient outcome. Using in vitro as well as in vivo immunodeficient and immunocompetent murine MM models, we here show that BTZ also triggers immunogenic cell death (ICD) characterized by exposure of calreticulin (CALR) on dying MM cells, phagocytosis of tumor cells by dendritic cells, and induction of MM specific immunity. We identify a BTZ-triggered specific ICD-gene signature which confers improved outcome in two independent MM patient cohorts. Importantly, BTZ stimulates MM cells immunogenicity via activation of cGAS/STING pathway and production of type-I interferons; and STING agonists significantly potentiate BTZ-induced ICD. Our studies therefore delineate mechanisms whereby BTZ exerts immunotherapeutic activity, and provide the framework for clinical trials of STING agonists with BTZ to induce potent tumor-specific immunity and improve patient outcome in MM.
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Project description:We reported the living therapeutic system constructed by the engineered bacteria in photothermal hydrogel (EBPH) for metabolic regulating enhanced tumor immunotherapy (Fig 1). The Escherichia coli strain BL21(DE3) cells were employed and engineered to express lactate oxidase (LOX) and glucose oxidase (GOX) under the control of thermosensitive promoter. The rewired cells were encapsulated into the photothermal hydrogel formed by constructed with sodium alginate (SA) and polypyrrole (PPy). After injection the EBPH around the tumor, the in-situ expression of LOX and GOX was induced by the NIR-II laser irradiation at 1064 nm to catalyze the degradation of glucose and lactate. EBPH could regulate the energy metabolism of tumor cells and relieve the immunosuppressive TME. Meanwhile, EBPH stimulated a series of antitumor immunological responses including the effect of immunogenic cell death (ICD), the activation of cyclic guanosine monophosphate adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) pathway, the stimulation of T cells, the polarization of macrophages to M1 phenotype and the generation of memory T cells for long term tumor suppression. Our work establishes an approach of living therapeutic hydrogel for metabolic regulating enhanced tumor immunotherapy.
2025-03-28 | PXD062337 |
Project description:Immunogenic cell death (ICD) in cancer represents a functionally unique therapeutic response that can induce tumor-targeting immune responses. ICD is characterized by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which confer adjuvanticity to dying cancer cells. The spatiotemporally defined emission of DAMPs during ICD has been well described; whereas the epigenetic mechanisms that regulate ICD hallmarks have not yet been deeply elucidated. Here, we aimed to examine the involvement of miRNAs and their putative targets taking advantage from well-established in vitro models of ICD. To this end, B cell lymphoma (Mino) and breast cancer (MDA-MB-231) cell lines were exposed to two different ICD inducers: the combination of retinoic acid (RA) and interferon-alpha (IFN-a) and doxorubicin, and to non ICD inducers like gamma irradiation. Then, miRNA and mRNA profiles were studied by next generation sequencing. Co-expression analysis identified 16 miRNAs differentially modulated in cells subjected to ICD. Integrated miRNA-mRNA functional analysis revealed candidate miRNAs, mRNAs, and modulated pathways associated with Immune System Process (GO Term). In this sense, ICD induced a distinctive transcriptional signature hallmarked by regulation of antigen presentation, a crucial step for a proper immune system antitumor response activation. Interestingly, the major histocompatibility complex class I (MHC-I) pathway was upregulated whereas class II (MHC-II) was downregulated. Analysis of MHC-II associated transcripts and HLA-DR surface expression validated the inhibition of this pathway by ICD on lymphoma cells. miR-4284 and miR-212-3p were the strongest miRNAs upregulated by ICD associated with this event. It is well known that MHC-II expression on tumor cells facilitates the recruitment of CD4+ T cells. However, the interaction between tumor MHC-II and the inhibitory co-receptor LAG-3 on tumor-associated lymphocytes could provide an immunosuppressive signal that directly represses effector cytotoxic activity. In this context, MHC-II downregulation by ICD could enhance antitumor immunity. Overall, we found that the miRNA profile was significantly altered during ICD. Several miRNAs are predicted to be involved in the regulation of Class I and II MHC pathway, whose implication in ICD was demonstrated herein for the first time, which could eventually modulate tumor recognition and attack by the immune system.
2022-08-08 | E-MTAB-11799 | biostudies-arrayexpress